Alzheimer's disease is a dementing organic brain disorder occurring in both the presenile and senile age ranges. It is characterized histopathologically by senile plaque formation and neurofibrillary degeneration of an intensity that cannot be ascribed to the normal aging process. Over the past 5 years, a number of postmortem neurochemical studies have demonstrated a marked decrease of the biosynthetic enzyme for acetylcholine (ACh), choline acetyltransferase (CAT), in samples of hippocampus and neocortex from the cases of Alzheimer's disease. The reduction in cortical CAT activity has been shown to correlate both with the severity of dementia at the time of death and with the density of senile plaques in cerebral cortex. A prerequisite for the rational approach toward the pharmacotherapy of Alzheimer's disease is a thorough understanding of the anatomy and physiology of the cholinergic neurons innervating the neocortex and the hippocampus. Studies of the forebrain cholinergic system indicate that there are few, if any, intrinsic cholinergic cells within the cerebral cortex. Cholinergic projections to the neocortex arise from magnocellular nuclei of the basal forebrain (BFB) and there is a cholinergic pathway to the hippocampus from the septum. No systematic studies of ACh-containing cells have been reported. The aims of the present proposal are to study the physiology and pharmacology of ACh-containing neurons in the BFB. Specifically, it is an attempt to use combinations of techniques to identify and characterize the physiological properties of ACh-containing cells and then to elucidate specific neurotransmitters that might regulate or modulate the activity of ACh-containing cells. Ultimately such knowledge should help us to understand the pathogenesis of the Alzheimer's disease and lead to the development of new pharmacotherapy.